Cancer of the prostate is now the most commonly-diagnosed cancer in males. It is estimated that, in 1993, there will be 110,000 new cases of prostate cancer diagnosed in the U.S. alone, while 45,000 will die from this disease. Prostate cancer is now the third leading cause of all cancer-specific deaths in men between the ages of 55 and 74. It is projected that by the year 2000, a 90% increase in annual incidence of the disease and a 37% increase in annual mortality rates will be observed. Although prostate cancer may be a relatively indolent neoplasm in the elderly, the overall decrease in life span in patients with this disease is approximately 10 years.
Improvement in the treatment of prostate cancer has centered on early detection; in recent years, a screening test (prostate-specific antigen, or PSA), although not entirely specific, has increased the power to diagnose this disease in asymptomatic patients. Treatment of early prostate cancer in men under the age of 65 has focused on radical surgery and/or radiotherapy, but the impact of these aggressive approaches on overall survival remains debatable. The approach to treatment of men over the age of 65 historically has been more conservative, and is based on the ablation of testosterone production. This result is achieved by the administration of female hormones (estrogen) or by orchidectomy, often in combination with anti-androgen medication. More recently, luteinizing hormone-releasing hormone (LHRH) agonists have joined the hormonal armamentarium.
Hormone manipulation often may result in significant palliation of metastatic prostate cancer, with improvement of bone pain and other disease-associated symptoms, as well as a significant fall in PSA levels (usually indicative of a decrease in tumor mass). Despite initial improvement on hormonal treatment, a majority of patients with locally unresectable or metastatic disease will progress and fail to respond to further hormonal therapies. In this large group of patients, other forms of treatment are far less effective. Radiotherapy often may relieve the symptoms of bone pain, but is not curative. Over time, the disease will progress with a fatal outcome.
Over the last 20 years, there have been many attempts to treat metastatic non-hormonally responsive prostate cancer with cytotoxic chemotherapy drugs. The results have been uniformly unrewarding. For example, in a comprehensive review of chemotherapy trials published by Eisenberger in 1985, only 131 out of 1,683 (8%) evaluable patients treated with any form of chemotherapy had an objective response to treatment. The list of inactive agents is long and includes the drug cyclophosphamide. For example, Eisenberger's study revealed that none of 57 evaluable patients responded to cyclophosphamide as a single agent. When cyclophosphamide was combined with other drugs, including doxorubicin, 5-fluorouracil or cisplatinum, the overall objective response rate was 20 out of 142 patients (14%). Thus, the overall response to cyclophosphamide alone, or in combination with other agents, was only 20 out of 199 (10%). Recently, Smith el al reported a 40% response rate (4 of 10 patients) employing very high doses of cyclophosphamide (4.5 mg/M.sup.2) administered every 2 weeks in combination with granulocyte macrophage stimulating factor (GM-CSF); the latter was administered to counteract the severe myelosuppressive effects of this high dose of cyclophosphamide. Although not specifically reported, these patients also likely would have experienced significant nausea and vomiting and total loss of hair because of the dose of cyclophosphamide employed.
Thus, the analysis of several studies involving over 200 patients suggests that conventional doses of cyclophosphamide, administered alone or in combination with other cytotoxic chemotherapy drugs, are largely ineffective in the treatment of patients with hormone-refractory metastatic prostate cancer. Higher doses may be effective, but are associated with severe bone marrow depression, requiring the concomitant use of GM-CSF.